Therapies being investigated for Waldenström’s macroglobulinemia
Bhavesh Shah, RPh, BCOP: We’ve covered everything on BTK inhibitors. Let’s briefly touch on some of the future experimental agents and drugs you’re excited about in Waldenström’s macroglobulinemia. We have a BCL2 inhibitor and another exciting third generation BTK inhibitor, LOXO-305, which sounds really exciting. I don’t want to steal your thunder. I’m sure you have other drugs you want to talk about.
Steven Treon, MD, PhD, FACP, FRCP: Times are really exciting. What is important is that our pharmacist colleagues recognize that genomics-based biology is driving progress in this disease. Elevated levels of BCL2 are particularly seen in MYD88-patients mutated in their tumor cells. Venetoclax seems to be an excellent drug. Our study has just been accepted into the JCO [Journal of Clinical Oncology]. It’s online. In previously treated patients, we observed a major response rate of 80% and the median PFS [progression-free survival] in these patients was 30 months. It is important to keep in mind that many patients have seen a BTK inhibitor before and the levels of response were very similar. This gives us an option after a BTK inhibitor.
I mentioned earlier that CXCR4 is also a troublemaker. When you see CXCR4 in these patients, the response time is longer. They don’t get the depth of response, and they progress sooner. They are more likely to contract BTK CS481 mutations and becoming resistant. We recently published our trial with ulocuplumab. It is a CXCR4 antagonist antibody. Even though it’s a small trial and you can’t read much from it, we showed the response characteristics, including SSP data, to be what we would expect with someone which has wild type CXCR4. It was really a modification of the response to the treatment. We are excited about the development of the CXCR4 antagonist.
There is also an oral antagonist, mavorixafor, against CXCR4 which is in clinical trial. We have reported some of the preliminary safety data to the EHA [European Hematology Association Congress], and we got a bit more about that at ASH [American Society of Hematology Annual Meeting].
Pirtobrutinib, which you mentioned, is a non-covalent BTK inhibitor. We are excited about this drug because it gives us another option for someone who develops a BTK CS481 mutation. My friend and colleague Michael Wang at [The University of Texas] MD Anderson [Cancer Center] did a very large study including patients with Waldenstrom’s macroglobulinemia. They found a 60% response rate in their Waldenström patients treated with a BTK inhibitor. We are doing a big test validating these initial observations. We will continue to be able to exploit these drugs. My colleague Jorge Castillo combines ibrutinib and venetoclax. It’s a big trial. I also see zanubrutinib and BCL2 inhibitors combine. We will optimize these drugs. It’s not just about introducing new drugs into the sphere. It optimizes them in order to have a better effect on the disease.
Bhavesh Shah, RPh, BCOP: We continue to improve BTK inhibitors, with the third generation BTK inhibitor you mentioned having an overall response rate of 60% and an adverse effect profile that seems amazing compared to current agents. From the perspective of the pharmacist and provider, having something that has minimal grade 3 or 4 toxicity, and maybe even grade 2, seems to be very tolerable. I can’t wait to see these agents.
Steven Treon, MD, PhD, FACP, FRCP: I am impressed by the absence of atrial fibrillation [AFib] this has also been observed with pirtobrutinib or LOXO-305. The number of studies is still relatively small. There are always hundreds of us, but it’s cool to see that there could also be a difference in AFib. It’s an exciting time. This is the perfect time to be in oncology. I’m sure for the next generation it will be bigger, but look at what all this basic science has taught us and continues to teach us.
Bhavesh Shah, RPh, BCOP: We’re out of time, so I want to thank you and our viewers. I hope you found this Pharmacy hours® Knowledge be rich and informative.
Steven Treon, MD, PhD, FACP, FRCP: Also.
Transcript edited for clarity.